Abstract

Introduction

Women with pathogenic germline gene variants in BRCA1 and/or BRCA2 are at increased risk of developing ovarian and breast cancer. While surgical and pharmacological approaches are effective for risk-reduction, it is unknown whether lifestyle approaches such as healthful dietary habits, weight management, and physical activity may also contribute to risk-reduction. We conducted a systematic review of evidence related to dietary habits, weight status/change, and physical activity on ovarian and breast cancer risk among women with BRCA1/2 pathogenic variants.

Methods

We searched Medline, EMBASE, CENTRAL, PubMed, and clinicaltrials.gov up to October 3, 2019. We identified 2775 records and included 21.

Results

There is limited evidence related to these factors and ovarian cancer risk. For breast cancer risk, evidence suggests higher diet quality, adulthood weight-loss of ≥10 pounds, and activity during adolescence and young-adulthood may be linked with decreased risk. Higher meat intake and higher daily energy intake may be linked with increased risk.

Conclusions

There is not enough evidence to suggest tailored recommendations for dietary habits or weight management among women with BRCA1/2 pathogenic variants compared to the general population for ovarian and breast cancer risk-reduction, and physical activity recommendations should remain the same.

Background

The estimated risk up to 80 years of age for ovarian and breast cancer among women with BRCA1 and BRCA2 pathogenic germline gene variants is 44 and 72% respectively for BRCA1 and 17 and 69% respectively for BRCA2 [1]. Effective surgical and pharmacological approaches are available for risk-reduction, such as risk-reducing surgery in the context of both breast and ovarian cancer, chemoprevention in the context of breast cancer, and oral contraceptive use in the context of ovarian cancer [2, 3]. What is currently unknown is whether complementary lifestyle approaches such as dietary habits, weight management, and physical activity (PA) may also contribute to cancer risk-reduction among this group of high-risk women.

To date, there are five reviews evaluating the impact of either dietary habits, weight management, or PA, or a combination of only two of these factors (i.e. diet and weight), on ovarian and/or breast cancer risk among women with BRCA1/2 pathogenic germline gene variants from 1997 to 2015 [3,4,5,6,7]. Four of the five previous reviews included women with BRCA1 and BRCA2 pathogenic germline gene variants, but only in the context of breast cancer risk [3, 5,6,7]. And only one review assessed ovarian cancer risk, and this was only in relation to alcohol intake [6]. No studies have exclusively evaluated healthful dietary habits, weight management, and PA together as they relate to both ovarian and breast cancer risk in this high-risk population.

The purpose of the current systematic review was to explore the state of evidence related to these lifestyle factors and ovarian and breast cancer risk among women with BRCA1/2 pathogenic germline gene variants, in order to determine the extent to which lifestyle recommendations should differ compared to the general population.

Methods

Search strategy

The search terms and search strategy were developed by four authors (AMC, LG, KBE, KJK), one of whom (KJK) is a medical research librarian specializing in systematic reviews. A systematic search was performed in MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov from inception to October 3, 2019. Search structures, subject headings, and keywords were tailored to each database by KJK. The search was expanded through citation chaining (forward and backward) of included studies. The search terms used can be found in the MEDLINE search strategy [see Additional File 1]. Findings are reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [8](Fig. 1). The protocol is registered in PROSPERO(ID:CRD42017060007).

Review process, selection Criteria & Data Extraction

Two authors (AMC, LG) independently screened the titles and abstracts of the articles to identify potentially relevant studies. Studies that passed the title/abstract review were retrieved for full-text review. Disagreements were resolved by consensus and by seeking the opinion of a third author (KBE). Inclusion criteria consisted of studies that: included individuals with BRCA1/2 pathogenic germline gene variants; evaluated weight status, weight change, dietary habits (as defined by dietary patterns, food and beverage intake, multivitamin and mineral supplementation), or physical activity in relation to ovarian or breast cancer risk; published in English; and included human subjects only.

Analysis

Qualitative synthesis of data is provided in narrative form. A meta-analysis was not conducted due to the limited number of studies and heterogeneity in study design and outcome measures.

Results

Risk-of-Bias summary

Table 1 provides details of the risk of bias assessment for all studies. Four studies received an overall quality score of strong [11,12,13,14], 16 received moderate [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29], and one received weak [30].

Physical activity

Studies assessing PA, evaluated activity across varying time periods, among women with BRCA1/2 pathogenic germline gene variants collectively. Among Ashkenazi Jewish women, engagement in PA as a teenager was associated with delayed onset of breast cancer [17]. Nkondjock and colleagues [31] did not observe significant associations between PA variables two years before breast cancer diagnosis and breast cancer risk.

Alternatively, Lammert and colleagues [13] and Pijpe and colleagues [25] evaluated PA over longer periods of time. Lammert and colleagues [13] case-control study among 433 women with BRCA1/2 pathogenic germline gene variants assessed PA in adolescence and early adulthood and adjusted analyses for number of children, current BMI, history of oral contraceptive use and/or oophorectomy, and tobacco consumption. Pijpe and colleagues [25] retrospective cohort among 725 women with BRCA1/2 pathogenic germline gene variants assessed lifetime sports activity and adjusted for oral contraceptives, parity, menopausal status, hormone replacement therapy, age-specific BMI, BMI at age 18, alcohol consumption, occupational activity. In certain analyses, mean metabolic equivalent (MET)-hours/week and mean hours/week were adjusted for number of active years, and number of active years were also adjusted for mean MET-hours/week.

Lammert and colleagues [13] assessed moderate, vigorous, and total activity in MET-hours/week in adolescence, young adulthood, and overall. Analysis was also stratified by menopausal status at diagnosis. The only association observed was for the highest quartile of moderate activity in adolescence, > 25.88 MET-hours/week, in relation to premenopausal breast cancer risk (HR 0.62, 95%CI 0.40,0.96) [13].

Pijpe and colleagues [25] assessed lifetime sports activity overall, before and after age 30, and in time windows (one-year, two-, five-, and 10-years) before age 35. Overall, 11–22.7 MET-hours/week of sports activity was associated with a 41% reduction in risk (HR 0.59, 95%CI 0.36,0.95), whereas ≥22.7 MET-hours/week was not associated with reduced risk (HR 0.77, 95%CI 0.8,1.24) [25]. When never engaging in sports activity was the reference, significant associations were not observed [25].

Before age 30, when the lowest sports activity category was used as the reference, 11–22.7 and ≥ 22.7 mean MET-hours/week was associated with a 40% reduction in breast cancer risk [9, 25]. Associations were not observed when never-engaging in sports activity was used as the reference category. In contrast, after age 30, ever-engaging in sports activity was associated with a 37% reduction in breast cancer risk (HR 0.63, 95%CI 0.44,0.91 [25]. When never-engaging in sports activity was the reference category, significant associations were only observed for the lowest category (least amount of activity) of each variable [32].

Table 3 provides a summary of results for diet, weight, and PA in relation to ovarian and breast cancer risk among women with BRCA1/2 pathogenic germline gene variants.

Evidence is limited related to food/nutrient intake and breast cancer risk among women with BRCA1/2 pathogenic germline gene variants [12, 14, 27, 31]. An association was not observed with vegetable intake [12], and findings for micronutrients are mixed, pending the nutrient [27, 31]. Among the general population, evidence is limited and inconclusive regarding the relationship between non-starchy vegetables, nutrients, and breast cancer risk [34].

Regarding PA, activity in adolescence and lifetime activity appear to have some association with breast cancer risk-reduction among women with BRCA1/2 pathogenic germline gene variants collectively [13, 25]. This notion is supported by evidence from the general population, such that it is probable that PA, regardless of intensity, reduces postmenopausal risk and vigorous-intensity activity reduces premenopausal risk [34]. Thus, activity recommendations should remain consistent with recommendations for the general population.

This is the first study to our knowledge to systematically evaluate whether tailored recommendations related to dietary habits, weight management and PA may be effective in reducing ovarian and breast cancer risk among women with BRCA1/2 pathogenic germline gene variants. We consider the following factors limitations of the current state of evidence: small number of studies for both ovarian and breast cancer risk in this high risk population, especially when considering the available large epidemiological studies that have established associations of lifestyle factors among the general population; heterogeneity in methods to evaluate lifestyle factors; inconsistent confounding factors; no data evaluating hormone receptor status; limited data evaluating by gene variant and menopausal status. Considering these limitations, notably the heterogeneity of the current evidence, inability to separate analyses by BRCA1/2 pathogenic germline gene variant, and retrospective nature of the majority of studies conducted, it is difficult to determine the extent of which recommendations for lifestyle factors should differ for this higher risk population. Future observational studies should address these limitations, specifically prospective, larger cohort studies enabling one to assess risk for these factors by gene variant.

Conclusions

Among women with BRCA1/2 pathogenic germline gene variants, there is insufficient evidence for recommendations related to dietary habits or weight management and ovarian cancer risk. Pertaining to breast cancer, there is not enough evidence to suggest variation from current recommendations for the general population for dietary habits or weight management. There is no evidence to suggest that risk association related to physical activity differed from the general population; therefore, recommendations for physical activity should remain the same.

Acknowledgements & Footnotes

Not applicable

Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R25CA057730 (PI: Shine Chang, PhD), by the Center for Energy Balance in Cancer Prevention and Survivorship, Duncan Family Institute for Cancer Prevention and Risk Assessment, and by MRSG-13-145-01 from the American Cancer Society.

Contributions

KBE conceptualized the paper. AMC, KJK, KBE and LAG developed the search strategy. KJK conducted the search, de-duplicated the data, and organized findings per PRISMA guidelines for AMC and LAG review. AMC and LAG conducted both rounds of review (abstract and full text reviews). AMC wrote the manuscript. All authors contributed to data interpretation and editing of the manuscript. All authors read and approve the final manuscript.

Author information

KJK is a research medical librarian who specializes in systematic reviews and meta-analyses.

Additional information

Publisher’s Note

Supplementary information

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